JP6462795B2 - LRRK2阻害薬としての新規な4−(置換アミノ)−7H−ピロロ[2,3−d]ピリミジン - Google Patents
LRRK2阻害薬としての新規な4−(置換アミノ)−7H−ピロロ[2,3−d]ピリミジン Download PDFInfo
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- JP6462795B2 JP6462795B2 JP2017150902A JP2017150902A JP6462795B2 JP 6462795 B2 JP6462795 B2 JP 6462795B2 JP 2017150902 A JP2017150902 A JP 2017150902A JP 2017150902 A JP2017150902 A JP 2017150902A JP 6462795 B2 JP6462795 B2 JP 6462795B2
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- Prior art keywords
- pyrrolo
- pyrimidin
- morpholin
- methyl
- pyrimidine
- Prior art date
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- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- JUQLTPCYUFPYKE-UHFFFAOYSA-N ritanserin Chemical compound CC=1N=C2SC=CN2C(=O)C=1CCN(CC1)CCC1=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 JUQLTPCYUFPYKE-UHFFFAOYSA-N 0.000 description 1
- 229950009626 ritanserin Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 229940106905 robinul Drugs 0.000 description 1
- 102200092172 rs33949390 Human genes 0.000 description 1
- 102220010566 rs74163686 Human genes 0.000 description 1
- NEMGRZFTLSKBAP-LBPRGKRZSA-N safinamide Chemical compound C1=CC(CN[C@@H](C)C(N)=O)=CC=C1OCC1=CC=CC(F)=C1 NEMGRZFTLSKBAP-LBPRGKRZSA-N 0.000 description 1
- 229950002652 safinamide Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- CXYRUNPLKGGUJF-RAFJPFSSSA-M scopolamine methobromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)C)=CC=CC=C1 CXYRUNPLKGGUJF-RAFJPFSSSA-M 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229960003678 selegiline hydrochloride Drugs 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- BLFQGGGGFNSJKA-XHXSRVRCSA-N sertraline hydrochloride Chemical compound Cl.C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 BLFQGGGGFNSJKA-XHXSRVRCSA-N 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 229940001089 sinemet Drugs 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229950007874 solanezumab Drugs 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 1
- 229950001675 spiperone Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940000238 tasmar Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003777 thiepinyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 description 1
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 1
- 229960004523 tiletamine Drugs 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 229940041597 tofranil Drugs 0.000 description 1
- 229960002309 toloxatone Drugs 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960003570 tramiprosate Drugs 0.000 description 1
- 229940035321 transderm scop Drugs 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 229950005135 traxoprodil Drugs 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- WUHSWAJJIXAIGL-UHFFFAOYSA-N trimethyl-[2-(pyrrolo[2,3-d]pyrimidin-7-ylmethoxy)ethyl]silane Chemical compound N1=CN=C2N(COCC[Si](C)(C)C)C=CC2=C1 WUHSWAJJIXAIGL-UHFFFAOYSA-N 0.000 description 1
- AWCQRXQAKUSEBJ-UHFFFAOYSA-N trimethyl-[2-[[5-(1-methylpyrazol-4-yl)-4-morpholin-4-ylpyrrolo[2,3-d]pyrimidin-7-yl]methoxy]ethyl]silane Chemical compound C1=NN(C)C=C1C1=CN(COCC[Si](C)(C)C)C2=NC=NC(N3CCOCC3)=C12 AWCQRXQAKUSEBJ-UHFFFAOYSA-N 0.000 description 1
- DJGMAJUNGLCGPI-UHFFFAOYSA-N trimethyl-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-d]pyrimidin-7-yl]methoxy]ethyl]silane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CN(COCC[Si](C)(C)C)C2=NC=NC=C12 DJGMAJUNGLCGPI-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 108010084171 vanutide cridificar Proteins 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- 230000028973 vesicle-mediated transport Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- CKWXDLJHOHJWOX-UHFFFAOYSA-N voacangine hydroxyindolenine Natural products CCC1CC2N3CCC4(O)C(=Nc5ccc(OC)cc45)C2(CC1C3)C(=O)OC CKWXDLJHOHJWOX-UHFFFAOYSA-N 0.000 description 1
- 229940063674 voltaren Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229960002791 zimeldine Drugs 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
- 229940020965 zoloft Drugs 0.000 description 1
- 229940083488 zonalon Drugs 0.000 description 1
- 229940061740 zyvox Drugs 0.000 description 1
- XZVHHLNLLVICFA-SNVBAGLBSA-N α-difluoromethyl-dopa Chemical compound FC(F)[C@](C(O)=O)(N)CC1=CC=C(O)C(O)=C1 XZVHHLNLLVICFA-SNVBAGLBSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Description
R3が、1−メチルピラゾール−4−イル、1H−ピラゾール−4−イル、2−シアノピリジン−6−イル、3−メチル−1,2−チアゾール−5−イル、5−シアノ−1−メチルピロール−3−イル、3−メチルピリジン−5−イル、3−シアノフェニル、2−フルオロフェニル、3−フルオロフェニル、2,3−ジフルオロフェニル、2−フルオロ−5−クロロフェニル、2−フルオロ−3−シアノフェニルまたは2−メトキシ−5−フルオロフェニルであり、R4およびR5が、それぞれ独立に、水素またはメチルである、第一の態様の第1の実施形態の化合物または薬学的に許容できるその塩である。
R4およびR5が、それぞれ水素である、第9の実施形態の化合物または薬学的に許容できるその塩である。
5−(1−メチル−1H−ピラゾール−4−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
3−[6−メチル−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
6−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ピリジン−2−カルボニトリル;
3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−(ジメチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[(2S)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
(3−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}フェニル)メタノール;
4−(モルホリン−4−イル)−5−(1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
3−[2−メチル−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
{3−[4−(ジメチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]フェニル}メタノール;
3−[4−(3,3−ジメチルピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−(ピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
1−(5−フェニル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペリジン−3−カルボキサミド;
3−{4−[(3S)−3−ヒドロキシピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
4−[(3S)−3−メチルピペリジン−1−イル]−5−フェニル−7H−ピロロ[2,3−d]ピリミジン;
3−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
4−[(3S)−3−メチルピペリジン−1−イル]−5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−フェニル−4−(ピロリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン;
[1−(5−フェニル−7H−ピロロ[2,3−d]ピリミジン−4−イル)ピペリジン−4−イル]メタノール;
1−{5−[3−(ヒドロキシメチル)フェニル]−7H−ピロロ[2,3−d]ピリミジン−4−イル}ピペリジン−3−カルボニトリル;
1−[5−(3−シアノフェニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]ピペリジン−3−カルボニトリル;
4−(3,5−cis−ジメチルピペリジン−1−イル)−5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
4−メトキシ−3−[4−(3−メチルピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−(ジメチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−4−メトキシベンゾニトリル;
5−(5−クロロ−2−メトキシフェニル)−N,N−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−アミン;
3−{4−[4−(1H−イミダゾール−2−イル)ピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[3−(メトキシメチル)ピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−[4−(9−メチル−1−オキサ−4,9−ジアザスピロ[5.5]ウンデカ−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−(3−メトキシピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[2−(メトキシメチル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
N3−[5−(3−シアノフェニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]−N,N−ジメチル−β−アラニンアミド;
3−[4−(4,4−ジフルオロピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−(4−フルオロピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[4−(1H−ピラゾール−3−イル)ピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[(3S)−3−フルオロピロリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[2−(1H−ピラゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[3−(1H−ピラゾール−3−イル)ピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[3−(1H−イミダゾール−2−イル)ピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[(1−メチルピペリジン−3−イル)アミノ]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−[4−(3−オキソ−2,7−ジアザスピロ[4.5]デカ−7−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−((3R)−3−メチルピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−(4−{[2−(モルホリン−4−イル)エチル]アミノ}−7H−ピロロ[2,3−d]ピリミジン−5−イル)ベンゾニトリル;
3−[4−(2−オキサ−7−アザスピロ[4.5]デカ−7−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
N−{1−[5−(3−シアノフェニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]ピペリジン−4−イル}アセトアミド;
5−(1H−インダゾール−5−イル)−4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン;
3−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゼンスルホンアミド;
5−(2−フルオロフェニル)−4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン;
5−(1H−インダゾール−4−イル)−4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン;
5−(6−フルオロ−5−メチルピリジン−3−イル)−4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン;
5−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}−2,3−ジヒドロ−1H−イソインドール−1−オン;
4−[(3S)−3−メチルピペリジン−1−イル]−5−(ピリジン−3−イル)−7H−ピロロ[2,3−d]ピリミジン;
4−[(3S)−3−メチルピペリジン−1−イル]−5−(5−メチルピリジン−3−イル)−7H−ピロロ[2,3−d]ピリミジン;
4−[(3S)−3−メチルピペリジン−1−イル]−5−(7H−ピロロ[2,3−b]ピリジン−5−イル)−7H−ピロロ[2,3−d]ピリミジン;
6−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}−2,3−ジヒドロ−1H−イソインドール−1−オン;
4−[(3S)−3−メチルピペリジン−1−イル]−5−(1H−ピロロ[3,2−b]ピリジン−6−イル)−7H−ピロロ[2,3−d]ピリミジン;
4−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}フェノール;
4−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンズアミド;
3−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}フェノール;
5−(2−クロロ−5−メチルピリジン−3−イル)−4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン;
3−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンズアミド;
3−[4−(3−フルオロピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−(4−メチルピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}安息香酸;
3−[4−(メチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−(3,5−cis−ジメチルピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−4−メトキシベンゾニトリル;
4−メトキシ−3−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
2−フルオロ−3−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
N,N−ジメチル−5−フェニル−7H−ピロロ[2,3−d]ピリミジン−4−アミン;
3−[4−(ジメチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−2−フルオロベンゾニトリル;
3−[4−(ピロリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−((3R)−3−メチルピロリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−(ジメチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−4−フルオロベンゾニトリル;
3−[4−(ジエチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[(2R)−2−(メトキシメチル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−[4−(ジメチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−5−フルオロベンゾニトリル;
3−{4−[2−(1H−ピラゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−[4−((3S)−3−メチルピロリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
2−フルオロ−3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[(2R)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
4−フルオロ−3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
4−(4−フルオロピペリジン−1−イル)−5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
2−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
5−(3−クロロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(2−フルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−フルオロ−5−メトキシフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(2,5−ジフルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(2,3−ジフルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(5−クロロ−2−フルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
{2−フルオロ−3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]フェニル}メタノール;
5−(2,4−ジフルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−フルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3,5−ジフルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
4−(モルホリン−4−イル)−5−フェニル−7H−ピロロ[2,3−d]ピリミジン;
5−(5−フルオロ−2−メトキシフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(2−クロロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(5−フルオロ−2−メチルフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−メトキシフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
{2−フルオロ−5−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]フェニル}メタノール;
5−(4−フルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
{3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]フェニル}メタノール;
5−(2−メトキシフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−[3−(メチルスルファニル)フェニル]−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
4−(モルホリン−4−イル)−5−(ピリジン−3−イル)−7H−ピロロ[2,3−d]ピリミジン;
4−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]イソキノリン;
5−(5−ブロモピリジン−3−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(2−クロロ−5−メチルフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−メチルフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(1−メチル−1H−ピラゾール−3−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
3−[4−(4−ヒドロキシピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[2−(3−メチル−1,2,4−オキサジアゾール−5−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−メチル−5−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[2−(5−メチル−1,2,4−オキサジアゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−[4−(6−オキサ−3−アザビシクロ[3.1.1]ヘプタ−3−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−クロロ−5−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
4−メトキシ−3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
5−(5−クロロ−2−メトキシフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
6−メチル−5−(1−メチル−1H−ピラゾール−4−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
3−メトキシ−5−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
5−(1−メチル−1H−ピラゾール−4−イル)−4−(チオモルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
1−[5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]ピペリジン−3−オール;
4−[(2S)−2−メチルモルホリン−4−イル]−5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
4−[(2R)−2−メチルモルホリン−4−イル]−5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
4−(3−フルオロピペリジン−1−イル)−5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
{4−[5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]モルホリン−2−イル}メタノール;
5−(1−メチル−1H−ピラゾール−4−イル)−4−(2−{[(6−メチルピリジン−3−イル)オキシ]メチル}モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
N,N−ジメチル−5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン−4−アミン;
N−シクロプロピル−N−メチル−5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン−4−アミン;
3−[4−(3,3−ジフルオロピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−(3−アミノピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−[4−(2−{[5−(ジフルオロメチル)−1,2,4−オキサジアゾール−3−イル]メチル}モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[2−(1,3−チアゾール−2−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−[4−(4−オキソピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[4−フルオロ−4−(ヒドロキシメチル)ピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[2−(3−ヒドロキシフェニル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[2−(5−シクロプロピル−1,2,4−オキサジアゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−[4−(3,3−ジフルオロピロリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−(4−{2−[(3−シアノフェノキシ)メチル]モルホリン−4−イル}−7H−ピロロ[2,3−d]ピリミジン−5−イル)ベンゾニトリル;
3−[4−(3−ヒドロキシピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
1−[5−(3−シアノフェニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]ピペリジン−3−カルボキサミド;
3−[4−(2−エチルモルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[2−(ピリミジン−4−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[2−(3−シクロプロピル−1,2,4−オキサジアゾール−5−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−(4−{2−[(ジメチルアミノ)メチル]モルホリン−4−イル}−7H−ピロロ[2,3−d]ピリミジン−5−イル)ベンゾニトリル;
3−[4−(1H−ピラゾール−4−イルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−(4−{2−[(5−メチル−1,2,4−オキサジアゾール−3−イル)メチル]モルホリン−4−イル}−7H−ピロロ[2,3−d]ピリミジン−5−イル)ベンゾニトリル;
3−{4−[3−(5−メチル−1,3,4−オキサジアゾール−2−イル)ピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−[4−(ジメチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−5−メトキシベンゾニトリル;
5−(1−エチル−1H−ピラゾール−4−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(5−メチルピリジン−3−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(5−クロロピリジン−3−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(6−メトキシピラジン−2−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(1,3−ジメチル−1H−ピラゾール−4−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
3−{4−[(3S)−3−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
2−フルオロ−3−[2−メチル−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[(3R)−3−ヒドロキシピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
1−[5−(3−フルオロフェニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]ピペリジン−3−オール;
5−(5−フルオロ−2−メトキシフェニル)−4−[2−(5−メチル−1,2,4−オキサジアゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン;
2−フルオロ−3−[4−(4−フルオロピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
4−(4−フルオロピペリジン−1−イル)−5−(2−メトキシフェニル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−フルオロ−5−メトキシフェニル)−4−(4−フルオロピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン;
3−[4−(4,4−ジフルオロピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−2−フルオロベンゾニトリル;
1−[5−(5−メチルピリジン−3−イル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]ピペリジン−3−オール;
5−(5−フルオロ−2−メトキシフェニル)−4−(4−フルオロピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン;
1−[5−(3−フルオロ−5−メトキシフェニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]ピペリジン−3−オール;
1−[5−(2−メトキシフェニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]ピペリジン−3−オール;
2−フルオロ−3−{4−[2−(3−メチル−1,2,4−オキサジアゾール−5−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
2−フルオロ−3−{4−[2−(メトキシメチル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
4−(アゼチジン−1−イル)−5−(5−フルオロ−2−メトキシフェニル)−7H−ピロロ[2,3−d]ピリミジン;
4−[(2S)−2−メチルモルホリン−4−イル]−5−(5−メチルピリジン−3−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−フルオロフェニル)−4−(ピロリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−フルオロフェニル)−4−[2−(5−メチル−1,2,4−オキサジアゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン;
5−(2−メトキシフェニル)−4−[(2S)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン;
5−(2−メトキシフェニル)−N,N−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−アミン;
2−フルオロ−3−{4−[(3S)−3−フルオロピロリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
4−[(3S)−3−フルオロピロリジン−1−イル]−5−(2−メトキシフェニル)−7H−ピロロ[2,3−d]ピリミジン;
5−(2−メトキシフェニル)−4−(ピロリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−フルオロ−5−メトキシフェニル)−N,N−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−アミン;
2−フルオロ−3−[4−(3−ヒドロキシピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
5−(5−フルオロ−2−メトキシフェニル)−4−[(2S)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン;
2−フルオロ−3−{4−[(2S)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
5−(5−フルオロ−2−メトキシフェニル)−4−(3−フルオロピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−フルオロフェニル)−4−[(2S)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン;
5−(5−フルオロ−2−メトキシフェニル)−N,N−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−アミン;
2−フルオロ−3−[4−(ピロリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
5−(5−フルオロ−2−メトキシフェニル)−4−[(3S)−3−フルオロピロリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン;
2−フルオロ−3−{4−[2−(5−メチル−1,2,4−オキサジアゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
5−(4−メチル−1,3−チアゾール−2−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(4−メチルピリジン−2−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(2−フルオロ−6−メトキシフェニル)−N,N−ジメチル−7H−ピロロ[2,3−d]ピリミジン−4−アミン;
5−(2−フルオロ−6−メトキシフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(2,6−ジフルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−メチル−1,2−チアゾール−5−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(2−クロロ−3−フルオロ−6−メトキシフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(4−メトキシピリジン−3−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
3−{4−[2−((5R)−5−メチル−1,2,4−オキサジアゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[2−((5S)−5−メチル−1,2,4−オキサジアゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
3−{4−[(2S)−2−(メトキシメチル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
からなる群から選択される、第一の態様の第1の実施形態の化合物または薬学的に許容できるその塩である。
5−(1−メチル−1H−ピラゾール−4−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
3−[6−メチル−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
6−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ピリジン−2−カルボニトリル;
3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
3−{4−[(2S)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
4−(モルホリン−4−イル)−5−(1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
3−[4−(ピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
2−フルオロ−3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
5−(2−フルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(2,3−ジフルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(5−クロロ−2−フルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3−フルオロフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(5−フルオロ−2−メトキシフェニル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
1−[5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]ピペリジン−3−オール;
5−(5−メチルピリジン−3−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
2−フルオロ−3−[4−(3−ヒドロキシピペリジン−1−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
2−フルオロ−3−{4−[(2S)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
2−フルオロ−3−{4−[2−(5−メチル−1,2,4−オキサジアゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
5−(3−メチル−1,2−チアゾール−5−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;および
3−{4−[2−(5−メチル−1,2,4−オキサジアゾール−3−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
からなる群から選択される、第一の態様の第1の実施形態の化合物または薬学的に許容できるその塩である。
3−[6−(ジフルオロメチル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
5−(5,6−ジヒドロ−2H−ピラン−3−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
5−(3,4−ジヒドロ−2H−ピラン−5−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
4−(モルホリン−4−イル)−5−[3−(1,2,4−オキサジアゾール−3−イル)フェニル]−7H−ピロロ[2,3−d]ピリミジン;
3−{4−[2−(3−メチル−1,2−オキサゾール−5−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
2−メチル−3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
4−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ピリジン−2(1H)−オン;
5−(イミダゾ[2,1−b][1,3]チアゾール−5−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
rel−3−{4−[(3aS,6aS)−ヘキサヒドロ−5H−フロ[2,3−c]ピロール−5−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
rel−3−{4−[(3aR,6aS)−テトラヒドロ−1H−フロ[3,4−c]ピロール−5(3H)−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
rel−3−{4−[(4aR,7aS)−ヘキサヒドロシクロペンタ[b][1,4]オキサジン−4(4aH)−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
4−[5−(3−シアノフェニル)−7H−ピロロ[2,3−d]ピリミジン−4−イル]モルホリン−2−カルボニトリル;
3−[4−(2,2−ジメチルモルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル;
5−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]チオフェン−2−カルボニトリル;
5−(イミダゾ[1,2−b]ピリダジン−3−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
2−フルオロ−3−{4−[2(R)−(3−メチル−1,2,4−オキサジアゾール−5−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
2−フルオロ−3−{4−[2(S)−(3−メチル−1,2,4−オキサジアゾール−5−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
6−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ピリジン−2−カルボキサミド;
4−(モルホリン−4−イル)−5−(ピラゾロ[1,5−a]ピリミジン−3−イル)−7H−ピロロ[2,3−d]ピリミジン;
1−メチル−4−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−1H−ピロール−2−カルボニトリル;
5−(6−メチルイミダゾ[2,1−b][1,3]チアゾール−5−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン;
3−{4−[2−(1,2−オキサゾール−5−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
1−メチル−4−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−1H−イミダゾール−2−カルボニトリル;
4−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]チオフェン−2−カルボニトリル;
4−(モルホリン−4−イル)−5−(ピラゾロ[1,5−a]ピリジン−3−イル)−7H−ピロロ[2,3−d]ピリミジン;
1,5−ジメチル−4−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−1H−ピロール−2−カルボニトリル;
1−メチル−3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]−1H−ピラゾール−5−カルボニトリル;および
3−{4−[2−(シアノメチル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル;
からなる群から選択される、第一の態様の第1の実施形態の化合物または薬学的に許容できるその塩である。
用語「アルキル」とは、直鎖または分枝鎖の飽和ヒドロカルビル置換基(すなわち、炭化水素から水素の除去によって得られる置換基)、一実施形態では、1個〜6個の炭素原子(すなわち、C1〜C6アルキル)、別の実施形態では、1個〜3個の炭素原子(すなわち、C1〜C3アルキル)を指す。このような置換基の例としては、メチル、エチル、プロピル(n−プロピルおよびイソプロピルを含める)、ブチル(n−ブチル、イソブチル、sec−ブチル、およびtert−ブチルを含める)、ペンチル、イソアミル、ヘキシルなどが挙げられる。
(i)単独またはドーパ脱炭酸酵素阻害薬(たとえば、カルビドパ(SINEMET、CARBILEV、PARCOPA)、ベンセラジド(MADOPAR)、α−メチルドパ、モノフルオロメチルドパ、ジフルオロメチルドパ、ブロクレシン、またはm−ヒドロキシベンジルヒドラジン)との組合せのレボドパ(またはそのメチルもしくはエチルエステル)、
(ii)抗コリン薬、たとえば、アミトリプチリン(ELAVIL、ENDEP)、ブトリプチリン、メシル酸ベンズトロピン(COGENTIN)、トリヘキシフェニジル(ARTANE)、ジフェンヒドラミン(BENADRYL)、オルフェナドリン(NORFLEX)、ヒヨスチアミン、アトロピン(ATROPEN)、スコポラミン(TRANSDERM−SCOP)、スコポラミンメチルブロミド(PARMINE)、ジシクロベリン(BENTYL、BYCLOMINE、DIBENT、DILOMINE)、トルテロジン(DETROL)、オキシブチニン(DITROPAN、LYRINEL XL、OXYTROL)、ペンチエナートブロミド、プロパンテリン(PRO−BANTHINE)、シクリジン、イミプラミン塩酸塩(TOFRANIL)、イミプラミンマレイン酸塩(SURMONTIL)、ロフェプラミン、デシプラミン(NORPRAMIN)、ドキセピン(SINEQUAN、ZONALON)、トリミプラミン(SURMONTIL)、グリコピロレート(ROBINUL)、
(iii)カテコールO−メチル基転移酵素(COMT)阻害薬、たとえば、ニテカポン、トルカポン(TASMAR)、エンタカポン(COMTAN)、トロポロン、
(iv)モノアミン酸化酵素(MAO)阻害薬、たとえば、セレギリン(EMSAM)、セレギリン塩酸塩(l−デプレニル、ELDEPRYL、ZELAPAR)、ジメチルセレギリン、ブロファロミン、フェネルジン(NARDIL)、トラニルシプロミン(PARNATE)、モクロベミド(AURORIX、MANERIX)、ベフロキサトン、サフィナミド、イソカルボキサジド(MARPLAN)、ニアラミド(NIAMID)、ラサギリン(AZILECT)、イプロニアジド(MARSILID、IPROZID、IPRONID)、イプロクロジド、トロキサトン(HUMORYL、PERENUM)、ビフェメラン、デソキシペガニン、ハルミン(テレパチンまたはバナステリンとしても知られる)、ハルマリン、リネゾリド(ZYVOX、ZYVOXID)、パルギリン(EUDATIN、SUPIRDYL)、
(v)アセチルコリンエステラーゼ阻害薬、たとえば、ドネペジル塩酸塩(ARICEPT(登録商標)、MEMAC)、サリチル酸フィゾスチグミン(ANTILIRIUM(登録商標))、硫酸フィゾスチグミン(ESERINE)、ガンスチグミン、リバスチグミン(EXELON(登録商標))、ラドスチギル、NP−0361、ガランタミン臭化水素酸塩(RAZADYNE(登録商標)、REMINYL(登録商標)、NIVALIN(登録商標))、タクリン(COGNEX(登録商標))、トルセリン、メモクイン、フペルジンA(HUP−A、Neuro−Hitech)、フェンセリン、ビスノルシムセリン(BNCとしても知られる)、INM−176、
(vi)アミロイドβ(またはその断片)、たとえば、HLA DR結合性エピトープ(PADRE(登録商標))と複合化したAβ1−15、ACC−001(Elan/Wyeth)、Affitope、
(vii)アミロイドβ(またはその断片)に対する抗体、たとえば、ポネズマブ、ソラネズマブ、バピネオズマブ(AAB−001としても知られる)、AAB−002(Wyeth/Elan)、ガンテネルマブ、静脈内Ig(GAMMAGARD(登録商標))、LY2062430(ヒト化m266、Lilly)、ならびに国際特許公開第WO04/032868号、WO05/025616号、WO06/036291号、WO06/069081号、WO06/118959号、米国特許公開第US2003/0073655号、US2004/0192898号、US2005/0048049号、US2005/0019328号、欧州特許公開第EP0994728号および1257584号、および米国特許第5,750,349号で開示されているもの;
(viii)アミロイドを低減または阻害する薬剤(アミロイド産生、蓄積、および線維化を低減するものを含める)、たとえば、エプロジセート、セレコキシブ、ロバスタチン、アナプソス、コロストリニン、ピオグリタゾン、クリオキノール(PBT1としても知られる)、PBT2(Prana Biotechnology)、フルルビプロフェン(ANSAID(登録商標)、FROBEN(登録商標))およびそのR−鏡像異性体タレンフルルビル(FLURIZAN(登録商標))、ニトロフルルビプロフェン、フェノプロフェン(FENOPRON、NALFON(登録商標))、イブプロフェン(ADVIL(登録商標)、MOTRIN(登録商標)、NUROFEN(登録商標))、イブプロフェンリシン塩、メクロフェナム酸、メクロフェナム酸ナトリウム(MECLOMEN(登録商標))、インドメタシン(INDOCIN(登録商標))、ジクロフェナクナトリウム(VOLTAREN(登録商標))、ジクロフェナクカリウム、スリンダク(CLINORIL(登録商標))、スリンダク硫化物、ジフルニサル(DOLOBID(登録商標))、ナプロキセン(NAPROSYN(登録商標))、ナプロキセンナトリウム(ANAPROX(登録商標)、ALEVE(登録商標))、インスリン分解酵素(インスリシンとしても知られる)、イチョウ抽出物EGb−761(ROKAN(登録商標)、TEBONIN(登録商標))、トラミプロセート(CEREBRIL(登録商標)、ALZHEMED(登録商標))、KIACTA(登録商標))、ネプリライシン(中性エンドペプチダーゼ(NEP)としても知られる)、シロイノシトール(シリトールとしても知られる)、アトルバスタチン(LIPITOR(登録商標))、シンバスタチン(ZOCOR(登録商標))、メシル酸イブタモレン、BACE阻害薬、たとえば、LY450139(Lilly)、BMS−782450、GSK−188909;γセクレターゼ修飾薬および阻害薬、たとえば、ELND−007、BMS−708163(アバガセスタット)、DSP8658(Dainippon);RAGE(終末糖化産物の受容体)阻害薬、たとえば、TTP488(Transtech)およびTTP4000(Transtech)や、PTI−777を含めた米国特許第7,285,293号で開示されているもの、
(ix)α−アドレナリン受容体作動薬およびβ−アドレナリン受容体遮断薬(β遮断薬)、抗コリン薬、抗痙攣薬、抗精神病薬、カルシウムチャネル遮断薬、カテコールO−メチル基転移酵素(COMT)阻害薬、中枢神経系刺激薬、副腎皮質ステロイド、ドーパミン受容体作動薬および拮抗薬、ドーパミン再取込み阻害薬、γ−アミノ酪酸(GABA)受容体作動薬、免疫抑制薬、インターフェロン、ムスカリン受容体作動薬、神経保護薬、ニコチン受容体作動薬、ノルエピネフリン(ノルアドレナリン)再取込み阻害薬、キノリン、栄養性因子、
(x)ヒスタミン3(H3)拮抗薬、たとえば、PF−3654746、ならびに米国特許公開第US2005−0043354号、US2005−0267095号、US2005−0256135号、US2008−0096955号、US2007−1079175号、およびUS2008−0176925号、国際特許公開第WO2006/136924号、WO2007/063385号、WO2007/069053号、WO2007/088450号、WO2007/099423号、WO2007/105053号、WO2007/138431号、およびWO2007/088462号、米国特許第7,115,600号で開示されているもの、
(xi)N−メチル−D−アスパラギン酸(NMDA)受容体拮抗薬、たとえば、メマンチン(NAMENDA、AXURA、EBIXA)、アマンタジン(SYMMETREL)、アカンプロセート(CAMPRAL)、ベソンプロジル、ケタミン(KETALAR)、デルセミン、デキサナビノール、デキセファロキサン、デキストロメトルファン、デキストロルファン、トラキソプロジル、CP−283097、ヒマンタン、イダンタドール、イペノキサゾン、L−701252(Merck)、ランシセミン、レボルファノール(DROMORAN)、メサドン、(DOLOPHINE)、ネラメキサン、ペルジンホテル、フェンシクリジン、チアネプチン(STABLON)、ジゾシルピン(MK−801としても知られる)、イボガイン、ボアカンギン、チレタミン、リルゾール(RILUTEK)、アプチガネル(CERESTAT)、ガベスチネル、レマシミド、
(xii)(a)PDE1阻害薬、(b)PDE2阻害薬、(c)PDE3阻害薬、(d)PDE4阻害薬、(e)PDE5阻害薬、(f)PDE9阻害薬(たとえば、PF−04447943、BAY73−6691(Bayer AG)、および米国特許公開第US2003/0195205号、US2004/0220186号、US2006/0111372号、US2006/0106035号、および(2008年5月9日出願の)USSN12/118,062号で開示されているもの)、および(g)PDE10阻害薬、たとえば、2−({4−[1−メチル−4−(ピリジン−4−イル)−1H−ピラゾール−3−イル]フェノキシ}メチル)キノリン(PF−2545920)を始めとする、ホスホジエステラーゼ(PDE)阻害薬、
(xiii)セロトニン(5−ヒドロキシトリプタミン)1A(5−HT1A)受容体拮抗薬、たとえば、スピペロン、levo−ピンドロール、レコゾタン、
(xiv)セロトニン(5−ヒドロキシトリプタミン)2C(5−HT2c)受容体作動薬、たとえば、バビカセリン、ジクロナピン;セロトニン(5−ヒドロキシトリプタミン)4(5−HT4)受容体作動薬/拮抗薬、たとえば、PRX−03140(Epix)およびPF−04995274、
(xv)セロトニン(5−ヒドロキシトリプタミン)3C(5−HT3c)受容体拮抗薬、たとえば、オンダンセトロン(Zofran)、
(xvi)セロトニン(5−ヒドロキシトリプタミン)6(5−HT6)受容体拮抗薬、たとえば、ミアンセリン(TOLVON、BOLVIDON、NORVAL)、メチオテピン(メチテピンとしても知られる)、リタンセリン、SB−271046、SB−742457(GlaxoSmithKline)、Lu AE58054(Lundbeck A/S)、SAM−760、PRX−07034(Epix)、
(xvii)セロトニン(5−HT)再取込み阻害薬、たとえば、アラプロクラート、シタロプラム(CELEXA、CIPRAMIL)、エスシタロプラム(LEXAPRO、CIPRALEX)、クロミプラミン(ANAFRANIL)、デュロキセチン(CYMBALTA)、フェモキセチン(MALEXIL)、フェンフルラミン(PONDIMIN)、ノルフェンフルラミン、フルオキセチン(PROZAC)、フルボキサミン(LUVOX)、インダルピン、ミルナシプラン(IXEL)、パロキセチン(PAXIL、SEROXAT)、セルトラリン(ZOLOFT、LUSTRAL)、トラゾドン(DESYREL、MOLIPAXIN)、ベンラファキシン(EFFEXOR)、ジメリジン(NORMUD、ZELMID)、ビシファジン、デスベンラファキシン(PRISTIQ)、ブラソフェンシン、ビラゾドン、カリプラジン、テソフェンシン、
(xviii)グリシン輸送体1阻害薬、たとえば、パリフルチン、ORG−25935、ORG−26041、およびmGluR修飾薬、たとえば、AFQ−059、アマンチジン、
(xix)AMPA型グルタミン酸受容体修飾薬、たとえば、ペランパネル、ミバンパトル、セルランパネル、GSK−729327、N−{(3S,4S)−4−[4−(5−シアノチオフェン−2−イル)フェノキシ]テトラヒドロフラン−3−イル}プロパン−2−スルホンアミド、
(xx)P450阻害薬、たとえば、リトナビル、
(xxi)tau治療ターゲット、たとえば、ダブネチド
など。
式Iの化合物は、以下で述べる方法、ならびに有機化学業界で知られている合成方法、または当業者によく知られている改変および変換によって調製することができる。本明細書で使用する出発材料は、市販品として入手可能であり、または当技術分野で知られている型通りの方法[Compendium of Organic Synthetic Methods、第I〜XII巻(Wiley−Interscience刊)などの標準参考書籍に記載の方法など]によって調製することもできる。好ましい方法としては、限定はしないが、以下に記載のものが挙げられる。
以下では、本発明の種々の化合物の合成を例示する。本発明の範囲内にある追加の化合物は、こうした実施例において例示する方法を、単独で使用するか、または当技術分野で一般に知られている技術と組み合わせて使用して、調製することができる。
5−ヨード−4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(P1)
4−クロロ−5−ヨード−7H−ピロロ[2,3−d]ピリミジン(9.8g、35mmol)のテトラヒドロフラン(250mL)溶液を0℃に冷却し、水素化ナトリウム(油中60%、1.54g、38.5mmol)で3回に分けて処理した。反応混合物を0℃で1時間撹拌しておいた後、2−(トリメチルシリル)エトキシメチルクロリド(6.4g、38mmol)を滴下し、反応混合物を室温に温め、3時間撹拌した。飽和塩化ナトリウム水溶液(250mL)で反応を失活させ、有機層を硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮した。シリカゲルクロマトグラフィー(溶離液:10:1の石油エーテル/酢酸エチル)にかけると、生成物が白色の固体として得られた。収率:8g、20mmol、57%。1H NMR (400MHz, DMSO-d6)δ8.69
(s, 1H), 8.14 (s, 1H), 5.60 (s, 2H), 3.51 (t, J=8Hz, 2H), 0.82 (t, J=8Hz, 2H),
-0.10 (s, 9H).
4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C1)(10.5g、25.6mmol)のn−ブタノール(300mL)溶液に、モルホリン(2.45g、28.1mmol)およびN,N−ジイソプロピルエチルアミン(6.63g、51.3mmol)を加え、反応混合物を還流温度で18時間加熱し、次いで減圧下で濃縮した。塩酸水溶液(0.1M、100mL)を加え、得られる固体を濾過によって収集し、水(20mL)で洗浄し、真空乾燥して、生成物を黄色の固体として得た。収率:8.0g、17mmol、66%。LCMS m/z 461.2 [M+H+]. 1H NMR (400MHz, DMSO-d6)δ8.39
(s, 1H), 7.81 (s, 1H), 5.52 (s, 2H), 3.80-3.86 (m, 4H), 3.46-3.53 (m, 6H),
0.77-0.84 (m, 2H), -0.10 (s, 9H).
4−(モルホリン−4−イル)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(P2)
(s, 1H), 7.73 (s, 1H), 5.59 (s, 2H), 3.87-3.93 (m, 4H), 3.68-3.74 (m, 4H),
3.49-3.56 (m, 2H), 1.35 (s, 12H), 0.87-0.93 (m, 2H), -0.06 (s, 9H).
5−ブロモ−4−クロロ−7−[(4−メチルフェニル)スルホニル]−7H−ピロロ[2,3−d]ピリミジン(P3)
(400MHz, DMSO-d6)δ8.84 (s, 1H), 8.42 (s, 1H), 8.06 (br d, J=8.4Hz,
2H), 7.46-7.51 (m, 2H), 2.37 (br s, 3H).
7−[(4−メチルフェニル)スルホニル]−4−(3−メチルピペリジン−1−イル)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−7H−ピロロ[2,3−d]ピリミジン(P4)
(s, 1H), 8.10 (br d, J=8.4Hz, 2H), 7.95 (s, 1H), 7.30 (br d, J=8.6Hz, 2H), 4.28
(br d, J=13Hz, 1H), 4.18-4.24 (m, 1H), 2.99 (ddd, J=13, 11, 4Hz, 1H), 2.70 (dd,
J=12.9, 10.9Hz, 1H), 2.40 (s, 3H), 1.77-1.85 (m, 1H), 1.56-1.70 (m, 4H), 1.35
(s, 12H), 0.88 (d, J=6.6Hz, 3H).
5−ヨード−4−[(3S)−3−メチルピペリジン−1−イル]−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(P5)
(s, 1H), 7.34 (s, 1H), 5.55 (s, 2H), 4.06-4.17 (m, 2H), 3.50-3.57 (m, 2H), 2.91
(ddd, J=12.6, 11.5, 3.5Hz, 1H), 2.58 (dd, J=12.6, 10.8Hz, 1H), 1.95-2.07 (m,
1H), 1.76-1.95 (m, 3H), 1.11-1.23 (m, 1H), 0.96 (d, J=6.8Hz, 3H), 0.88-0.94 (m,
2H), -0.04 (s, 9H).
4−クロロ−5−(1−メチル−1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン(P6)
4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C1)(4.1g、10mmol)、1−メチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1H−ピラゾール(2.1g、10mmol)、および炭酸カリウム(2.8g、20mmol)を1,4−ジオキサン水溶液に溶かした溶液に、ジクロロビス(トリフェニルホスフィン)パラジウム(II)(350mg、0.50mmol)を加えた。反応混合物を脱気し、窒素パージし、この手順を合計3回実施した。還流温度で18時間加熱した後、反応混合物を室温に冷却し、水(200mL)で希釈し、酢酸エチル(3×200mL)で抽出した。有機層を合わせて飽和塩化ナトリウム水溶液(500mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮した。シリカゲルでのクロマトグラフィー(勾配:0%〜10%の石油エーテル中酢酸エチル)によって精製すると、生成物が白色の固体として得られた。収率:2.0g、5.5mmol、55%。1H NMR (400MHz, CDCl3)δ8.66
(s, 1H), 7.68 (d, J=0.5Hz, 1H), 7.62 (br s, 1H), 7.36 (s, 1H), 5.68 (s, 2H),
3.99 (s, 3H), 3.54-3.59 (m, 2H), 0.91-0.97 (m, 2H), -0.03 (s, 9H).
実施例2で3−[6−メチル−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(2)の合成について記載した方法を使用して、4−クロロ−5−(1−メチル−1H−ピラゾール−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C2)を生成物に変換した。この場合では、黄色の固体として得た生成物を、分取HPLCではなく、酢酸エチルからの再結晶によって精製した。収率:1.0g、4.3mmol、2ステップで43%。LCMS m/z 234.0 [M+H+]. 1H NMR (400MHz, DMSO-d6)δ12.66
(br s, 1H), 8.58 (s, 1H), 7.91 (s, 1H), 7.69 (d, J=2.5Hz, 1H), 7.63 (d,
J=0.7Hz, 1H), 3.89 (s, 3H).
N,N−ジメチル−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−4−アミン(P7)
(s, 1H), 7.57 (s, 1H), 5.56 (s, 2H), 3.49-3.57 (m, 2H), 3.25 (s, 6H), 1.36 (s,
12H), 0.86-0.94 (m, 2H), -0.06 (s, 9H).
5−(1−メチル−1H−ピラゾール−4−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン(1)
5−ヨード−4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(P1)(500mg、1.1mmol)および1−メチル−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1H−ピラゾール(272mg、1.31mmol)をエタノールと水の混合物(4:1、10mL)に溶かした溶液に、ジクロロビス(トリフェニルホスフィン)パラジウム(II)(41mg、58μmol)および炭酸カリウム(447mg、3.23mmol)を加えた。反応混合物を脱気し、窒素パージし、この手順を合計3回実施した。次いでそれを100℃で18時間加熱した。真空中で濃縮した後、残渣をシリカゲルでのクロマトグラフィー(溶離液:1:1の酢酸エチル/石油エーテル)によって精製して、生成物を黄色の固体として得た。収率:200mg、0.48mmol、44%。1H NMR (400MHz, DMSO-d6)δ8.39
(s, 1H), 7.86 (s, 1H), 7.59 (s, 1H), 7.52 (s, 1H), 5.57 (s, 2H), 3.90 (s, 3H),
3.50-3.58 (m, 6H), 3.20-3.27 (m, 4H), 0.83 (dd, J=8.0, 7.9Hz, 2H), -0.09 (s,
9H).
5−(1−メチル−1H−ピラゾール−4−イル)−4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C4)(200mg、0.48mmol)のトリフルオロ酢酸(5mL)溶液を、室温で2時間撹拌した。反応混合物を減圧下で濃縮して、生成物を黄色の油状物として得、これをさらに精製することなく次のステップに使用した。
[5−(1−メチル−1H−ピラゾール−4−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−7−イル]メタノール(C5)(先行ステップからの材料、0.48mmol以下)のメタノール(5mL)溶液を、固体炭酸カリウムを加えることで、12より高いpHにした。反応混合物を30分間撹拌し、濾過し、真空中で濃縮した。分取HPLC(カラム:Agella Venusil ASB C18、5μm;移動相A:0.225%の水中ギ酸;移動相B:アセトニトリル、溶離液:13%のB)によって精製すると、生成物が黄色の固体として得られた。2ステップでの収率:90mg、0.32mmol、67%。LCMS m/z 285.1 [M+H+]. 1H NMR (400MHz, DMSO-d6)δ12.96
(br s, 1H), 8.47 (s, 1H), 7.85 (s, 1H), 7.57 (s, 1H), 7.52 (d, J=2.5Hz, 1H),
3.90 (s, 3H), 3.53-3.59 (m, 4H), 3.45-3.51 (m, 4H).
3−[6−メチル−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(2)
−78℃の4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C1)(15.0g、36.6mmol)のテトラヒドロフラン(500mL)溶液に、リチウムジイソプロピルアミド(2Mのヘプタン/テトラヒドロフラン/エチルベンゼン溶液、183mL、366mmol)を加え、反応混合物を−20℃で2時間撹拌し、次いで−78℃に冷却し直した。−78℃でヨードメタン(52.1g、367mmol)を加え、反応混合物を−20℃で2時間撹拌した。飽和塩化アンモニウム水溶液を加え、混合物を酢酸エチル(3×500mL)で抽出した。有機層を合わせて水(100mL)および飽和塩化ナトリウム水溶液(100mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮した。シリカゲルでのクロマトグラフィー(溶離液:10:1の石油エーテル/酢酸エチル)によって精製すると、生成物が黄色の油状物として得られた。収率:10g、24mmol、66%。LCMS m/z 424.1 [M+H+]. 1H NMR (400MHz, CDCl3)δ8.58
(s, 1H), 5.69 (s, 2H), 3.48-3.54 (m, 2H), 2.60 (s, 3H), 0.88-0.95 (m, 2H),
-0.05 (s, 9H).
4−クロロ−5−ヨード−6−メチル−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C6)(300mg、0.71mmol)および(3−シアノフェニル)ボロン酸(104mg、0.708mmol)を1,2−ジメトキシエタンと水の混合物(5:1、10mL)に溶かした溶液に、炭酸カリウム(193mg、1.40mmol)および[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(17mg、23μmol)を加えた。反応混合物を脱気し、窒素パージし、この手順を合計3回実施した。還流温度で18時間加熱した後、反応混合物を室温に冷却し、酢酸エチル(3×50mL)で抽出した。有機層を合わせて飽和塩化ナトリウム水溶液(50mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮した。シリカゲルクロマトグラフィー(勾配:0%〜20%の石油エーテル中酢酸エチル)によって精製すると、生成物が黄色の油状物として得られた。収率:140mg、0.351mmol、50%。LCMS m/z 399.2 [M+H+].
3−(4−クロロ−6−メチル−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル)ベンゾニトリル(C7)(140mg、0.351mmol)のn−ブタノール(5mL)溶液に、モルホリン(30.6mg、0.351mmol)およびN,N−ジイソプロピルエチルアミン(90.9mg、0.703mmol)を加えた。反応混合物を100℃で18時間加熱し、次いで真空中で濃縮して、生成物を黄色の固体として得た。収率:125mg、0.278mmol、79%。LCMS m/z 450.3 [M+H+].
3−[6−メチル−4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(C8)(125mg、0.278mmol)のトリフルオロ酢酸(10mL)溶液を、室温で2時間撹拌し、次いで真空中で濃縮して、生成物を黄色の固体(125mg)として得た。これをさらに精製することなく次のステップで使用した。LCMS m/z 349.9 [M+H+].
3−[7−(ヒドロキシメチル)−6−メチル−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(C9)(先行ステップより、125mg、0.278mmol以下)のアセトニトリル(5mL)溶液を、固体炭酸カリウムを加えることで、11より高いpHに調整した。混合物を濾過し、真空中で濃縮し、分取HPLC(カラム:Boston Symmetrix ODS−H、5μm;移動相A:0.225%の水中ギ酸;移動相B:アセトニトリル、勾配:19%〜39%のB)によって精製すると、生成物が黄色の固体として得られた。収率:54mg、0.17mmol、2ステップで61%。LCMS m/z 319.9 [M+H+]. 1H NMR (400MHz, DMSO-d6)δ12.17
(br s, 1H), 8.34 (s, 1H), 7.77-7.83 (m, 2H), 7.65-7.74 (m, 2H), 3.27-3.33 (m,
4H), 2.98-3.06 (m, 4H), 2.36 (s, 3H).
6−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ピリジン−2−カルボニトリル(3)
6−ブロモピリジン−2−カルボニトリル(80mg、0.44mmol)および4−(モルホリン−4−イル)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(P2)(241mg、0.523mmol)を1,4−ジオキサン(2.5mL)および水(0.5mL)に溶かした溶液に、テトラキス(トリフェニルホスフィン)パラジウム(0)(51mg、44μmol)および炭酸ナトリウム(140mg、1.32mmol)を加えた。反応混合物をマイクロ波照射のもと120℃で15分間加熱し、次いで水(30mL)で希釈し、酢酸エチル(3×50mL)で抽出した。有機層を合わせて飽和塩化ナトリウム水溶液(100mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮し、分取薄層クロマトグラフィー(溶離液:1:1の石油エーテル/酢酸エチル)によって精製すると、生成物が褐色の油状物として得られた。収率:110mg、0.252mmol、57%。1H NMR (400MHz, CDCl3)δ8.52
(s, 1H), 7.84-7.93 (m, 2H), 7.74 (s, 1H), 7.59 (dd, J=7.0, 1.2Hz, 1H), 5.66 (s,
2H), 3.56-3.65 (m, 6H), 3.34-3.40 (m, 4H), 0.93 (dd, J=8.3, 8.0Hz, 2H), -0.05
(s, 9H).
6−[4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル]ピリジン−2−カルボニトリル(C10)(110mg、0.252mmol)のトリフルオロ酢酸(3mL)溶液を、室温で2時間撹拌した。反応混合物を真空中で濃縮して、生成物を黄色の油状物として得、これをさらに精製することなく次のステップに使用した。
6−[7−(ヒドロキシメチル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ピリジン−2−カルボニトリル(C11)(先行ステップより、85mg、0.25mmol以下)のアセトニトリル(3mL)溶液を、固体炭酸カリウムを加えることで、12より高いpHにした。室温で30分経過後、反応混合物を濾過し、真空中で濃縮した。分取HPLC(カラム:Phenomenex Gemini C18、8μm;移動相A:水中アンモニア、pH10;移動相B:アセトニトリル、勾配:10%〜50%のB)によって精製すると、生成物が白色の固体として得られた。収率:15.2mg、49.6μmol、2ステップで20%。LCMS m/z 307.2 [M+H+].
1H NMR (400MHz, DMSO-d6)δ8.38 (s, 1H), 8.13 (dd, J=8.1,
7.7Hz, 1H), 7.96 (br d, J=8Hz, 1H), 7.89 (br d, J=8Hz, 1H), 7.86 (s, 1H),
3.50-3.55 (m, 4H), 3.19-3.24 (m, 4H).
3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(4)
4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C1)(8.2g、20mmol)、(3−シアノフェニル)ボロン酸(3.2g、22mmol)、および炭酸カリウム(8.3g、60mmol)を1,2−ジメトキシエタンと水の混合物(4:1の比率、250mL)に混ぜた撹拌した混合物に、[1,1’−ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)(731mg、1.00mmol)を加えた。反応混合物を脱気し、次いで窒素を投入し、この手順を合計3回実施した。反応混合物を還流温度で3時間加熱し、次いで室温に冷却し、飽和塩化ナトリウム水溶液(100mL)で希釈した。有機層を硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮した。シリカゲルカラムクロマトグラフィー(溶離液:10:1の石油エーテル/酢酸エチル)によって精製すると、生成物が黄色の油状物として得られた。収率:5.0g、12mmol、60%。1H NMR (400MHz, DMSO-d6)δ8.75
(s, 1H), 8.13 (s, 1H), 8.00-8.02 (m, 1H), 7.84-7.92 (m, 2H), 7.68 (dd, J=7.8,
7.8Hz, 1H), 5.70 (s, 2H), 3.60 (dd, J=8.0, 8.0Hz, 2H), 0.86 (dd, J=8.0, 8.0Hz,
2H), -0.08 (s, 9H).
3−(4−クロロ−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル)ベンゾニトリル(C12)(3.8g、9.9mmol)のトリフルオロ酢酸(25mL)溶液を、室温で2時間撹拌した。反応混合物を真空中で濃縮して、生成物(4g、100%を上回る質量回収率)を黄色の油状物として得、これをそれ以上精製せずに次のステップで使用した。
3−[4−クロロ−7−(ヒドロキシメチル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(C13)(先行ステップより4g、9.9mmol以下)のメタノール(100mL)溶液を、固体炭酸カリウムを加えることで、12より高いpHに調整した。真空中で溶媒を除去し、残渣を水(100mL)と混合した。得られる固体を濾過によって単離し、水で洗浄して、生成物を白色の固体として得た。収率:1.3g、5.1mmol、2ステップで52%。LCMS m/z 255.0 [M+H+].
3−(4−クロロ−7H−ピロロ[2,3−d]ピリミジン−5−イル)ベンゾニトリル(C14)(2.5g、9.8mmol)のn−ブタノール(100mL)溶液に、モルホリン(871mg、10mmol)およびN,N−ジイソプロピルエチルアミン(2.6g、20mmol)を加え、反応混合物を還流温度で3時間加熱した。真空中で溶媒を除去し、残渣を、シリカゲルでのクロマトグラフィー(溶離液:1:1の酢酸エチル/石油エーテル)を使用して精製した。引き続いて、酢酸エチルおよびtert−ブチルメチルエーテルから再結晶させると、生成物が白色の固体として得られた。収率:770mg、2.52mmol、26%。LCMS m/z 306.0 [M+H+]. 1H NMR (400MHz, DMSO-d6)δ12.34
(br s, 1H), 8.41 (s, 1H), 7.99-8.02 (m, 1H), 7.89 (br d, J=8Hz, 1H), 7.76 (br
d, J=7.5Hz, 1H), 7.71 (s, 1H), 7.68 (dd, J=7.8, 7.8Hz, 1H), 3.44-3.50 (m, 4H),
3.11-3.17 (m, 4H).
3−[4−(ジメチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(5)
(br s, 1H), 8.28 (s, 1H), 7.93 (br s, 1H), 7.78 (br d, J=7.8Hz, 1H), 7.73 (br
d, J=7.8Hz, 1H), 7.62 (br dd, J=8.0, 7.8Hz, 1H), 7.57 (br s, 1H), 2.73 (s, 6H).
3−{4−[(2S)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル(6)
NMR (400MHz, CDCl3)δ10.71 (br s, 1H), 8.53 (br s, 1H), 7.73-7.89 (m,
2H), 7.51-7.69 (m, 2H), 7.28 (s, 1H, 推定; 溶媒ピークにより一部不明確), 3.56-3.77 (m, 3H), 3.39-3.54 (m, 2H), 2.86-2.98 (m, 1H),
2.53-2.65 (m, 1H), 0.93-1.03 (m, 3H).
(3−{4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}フェニル)メタノール(7)
実施例6で3−{4−[(2S)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル(6)の調製について記載した方法に従って、5−ブロモ−4−クロロ−7−[(4−メチルフェニル)スルホニル]−7H−ピロロ[2,3−d]ピリミジン(P3)を、(3S)−3−メチルピペリジンの塩酸塩と反応させた。この場合では、精製をシリカゲルクロマトグラフィー(溶離液:5:1の石油エーテル/酢酸エチル)で実施して、生成物を白色の固体として得た。収率:4.3g、9.6mmol、92%。
5−ブロモ−7−[(4−メチルフェニル)スルホニル]−4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン(C15)(0.225g、0.501mmol)、[3−(ヒドロキシメチル)フェニル]ボロン酸(0.104g、0.684mmol)、炭酸ナトリウム(0.159g、1.50mmol)、およびジクロロビス(トリフェニルホスフィン)パラジウム(II)(36mg、51μmol)をアセトニトリル(2mL)および水(2mL)に混ぜた混合物を、15分間のマイクロ波照射のもと150℃に加熱した。反応液を真空中で濃縮して、生成物(0.35g、100%超)を得、これをさらに精製することなくそのまま次のステップで使用した。
先行ステップからの(3−{7−[(4−メチルフェニル)スルホニル]−4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}フェニル)メタノール(C16)(0.50mmol未満)の2−プロパノール(20mL)溶液を撹拌したものに、水酸化リチウム一水和物(0.42g、10mmol)および水(3mL)を加え、反応混合物を室温で18時間撹拌した。真空中で濃縮した後、残渣を分取HPLC(カラム:Waters XBridge;移動相A:0.1%の水中アンモニア;移動相B:アセトニトリル、勾配:44%〜60%のB)によって精製して、生成物を白色の固体として得た。収率:130mg、0.403mmol、2ステップで80%。LCMS m/z 323.4 [M+H+]. 1H NMR (400MHz, CD3OD)δ8.24
(s, 1H), 7.46 (br s, 1H), 7.35-7.43 (m, 2H), 7.30 (br d, J=6Hz, 1H), 7.23 (s,
1H), 4.67 (s, 2H), 3.89 (br d, J=13Hz, 1H), 3.79 (br d, J=12Hz, 1H), 2.58-2.69
(m, 1H), 2.27 (dd, J=12.0, 11.0Hz, 1H), 1.62-1.71 (m, 1H), 1.30-1.52 (m, 3H),
0.87-1.01 (m, 1H), 0.60 (d, J=6.5Hz, 3H).
4−(モルホリン−4−イル)−5−(1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン ギ酸塩(8)
4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1H−ピラゾール(10.0g、51.5mmol)のトルエン(200mL)溶液に、3,4−ジヒドロ−2H−ピラン(5.6g、67mmol)およびトリフルオロ酢酸(1.17g、10.3mmol)を加え、反応混合物を2時間90℃に加熱した。室温に冷却した後、反応混合物を酢酸エチル(200mL)と飽和炭酸水素ナトリウム水溶液(100mL)とに分配し、水層を酢酸エチル(100mL)で抽出した。有機層を合わせて飽和塩化ナトリウム水溶液(100mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮した。シリカゲルクロマトグラフィー(勾配:10%〜50%の石油エーテル中酢酸エチル)によって精製すると、生成物が白色の固体として得られた。収率:13.4g、48.2mmol、94%。1H NMR (400MHz, CDCl3)δ7.94
(s, 1H), 7.83 (s, 1H), 5.41 (dd, J=9.5, 2.5Hz, 1H), 4.01-4.08 (m, 1H),
3.65-3.74 (m, 1H), 1.98-2.18 (m, 3H), 1.6-1.76 (m, 3H), 1.32 (s, 12H).
4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C1)(2.0g、4.9mmol)、1−(テトラヒドロ−2H−ピラン−2−イル)−4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1H−ピラゾール(C17)(1.91g、6.87mmol)、リン酸カリウム(4.0g、19mmol)、およびテトラキス(トリフェニルホスフィン)パラジウム(0)(0.10g、87μmol)からなる混合物を、窒素で数回脱気し、マイクロ波合成装置において130℃で1.5時間照射にかけた。反応混合物を酢酸エチル(400mL)と水(60mL)とに分配し、水層を酢酸エチル(200mL)で抽出した。有機層を合わせて飽和塩化ナトリウム水溶液(100mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮した。シリカゲルでのクロマトグラフィー(勾配:10%〜80%の石油エーテル中酢酸エチル)にかけると、生成物が褐色の油状物として得られた。収率:1.33g、3.06mmol、62%。1H NMR (400MHz, CDCl3)δ8.67
(s, 1H), 7.87 (s, 1H), 7.76 (s, 1H), 7.38 (s, 1H), 5.68 (s, 2H), 5.46 (dd,
J=9.4, 2.9Hz, 1H), 4.08-4.15 (m, 1H), 3.71-3.79 (m, 1H), 3.57 (dd, J=8.3,
8.0Hz, 2H), 2.04-2.24 (m, 3H), 1.61-1.79 (m, 3H), 0.94 (dd, J=8.3, 8.3Hz, 2H),
-0.03 (s, 9H).
4−クロロ−5−[1−(テトラヒドロ−2H−ピラン−2−イル)−1H−ピラゾール−4−イル]−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C18)(3.3g、7.6mmol)、モルホリン(0.99g、11mmol)、およびN,N−ジイソプロピルエチルアミン(6mL、34mmol)のn−ブタノール(15mL)溶液を、マイクロ波合成装置において100℃で30分間照射にかけた。真空中で溶媒を除去した後、残渣をシリカゲルクロマトグラフィー(勾配:10%〜50%の石油エーテル中酢酸エチル)によって精製して、生成物を褐色の油状物として得た。収率:2.6g、5.4mmol、71%。1H NMR (400MHz, CDCl3)δ8.50
(s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.17 (s, 1H), 5.62 (s, 2H), 5.44 (dd,
J=6.5, 6.0Hz, 1H), 4.08-4.15 (m, 1H), 3.71-3.79 (m, 1H), 3.62-3.67 (m, 4H),
3.58 (dd, J=8.5, 8.0Hz, 2H), 3.33-3.39 (m, 4H), 2.06-2.19 (m, 3H), 1.62-1.79
(m, 3H), 0.93 (dd, J=8.5, 7.5Hz, 2H), -0.04 (s, 9H).
4−(モルホリン−4−イル)−5−[1−(テトラヒドロ−2H−ピラン−2−イル)−1H−ピラゾール−4−イル]−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C19)(4.0g、8.2mmol)のジクロロメタン(20mL)溶液に、塩化水素の1,4−ジオキサン溶液(4M、100mL)を加えた。反応混合物を室温で2時間撹拌し、次いで酢酸エチル(300mL)と飽和炭酸水素ナトリウム水溶液(300mL)の混合物中に注いだ。水層を酢酸エチル(2×300mL)で抽出し、有機層を合わせて飽和塩化ナトリウム水溶液(100mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、減圧下で濃縮した。シリカゲルクロマトグラフィー(勾配:10%〜80%の石油エーテル中酢酸エチル)によって精製すると、生成物が黄色の油状物として得られた。収率:2.18g、5.44mmol、66%。LCMS m/z 401.3 [M+H+]. 1H NMR (400MHz, CDCl3)δ8.51
(s, 1H), 7.78 (s, 2H), 7.19 (s, 1H), 5.64 (s, 2H), 3.56-3.66 (m, 6H), 3.34-3.40
(m, 4H), 0.91-0.98 (m, 2H), -0.03 (s, 9H).
4−(モルホリン−4−イル)−5−(1H−ピラゾール−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C20)(0.13g、0.32mmol)をトリフルオロ酢酸(10mL)に溶解させ、室温で2時間撹拌した。真空中で溶媒を除去すると、生成物(100mg)が褐色の固体として得られ、これをそれ以上精製せずに次のステップで使用した。LCMS m/z 301.2 [M+H+].
[4−(モルホリン−4−イル)−5−(1H−ピラゾール−4−イル)−7H−ピロロ[2,3−d]ピリミジン−7−イル]メタノール(C21)(先行ステップより、0.10g、0.32mmol以下)のアセトニトリル(10mL)溶液に、炭酸カリウム(0.34g、2.5mmol)を加え、反応混合物を室温で30分間撹拌した。混合物を濾過し、濾過ケークを酢酸エチル(3×20mL)で洗浄した。濾液を合わせて真空中で濃縮し、分取HPLC(カラム:DIKMA Diamonsil(2)C18、5μm;移動相A:0.225%の水中ギ酸;移動相B:アセトニトリル、勾配:0%〜17%のB)によって精製すると、生成物が淡色の固体として得られた。収率:36mg、0.11mmol、2ステップで34%。LCMS m/z 271.2 [M+H+]. 1H NMR (400MHz, CDCl3)δ10.72
(br s, 1H), 8.47 (s, 1H), 7.78 (s, 2H), 7.19 (s, 1H), 3.60-3.67 (m, 4H),
3.41-3.48 (m, 4H).
3−[2−メチル−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(9)
4−クロロ−2−メチル−7H−ピロロ[2,3−d]ピリミジン(400mg、2.4mmol)のジクロロメタン(10mL)溶液に、N−ヨードスクシンイミド(537mg、2.39mmol)を加えた。混合物を室温で2時間撹拌し、次いで亜硫酸ナトリウム水溶液で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮して、生成物を褐色の固体として得た。収率:330mg、1.12mmol、47%。LCMS m/z 293.8 [M+H+].
調製例P1において4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C1)の合成に使用した方法に従って、4−クロロ−5−ヨード−2−メチル−7H−ピロロ[2,3−d]ピリミジン(C22)を生成物に変換した。生成物は、黄色の油状物として得られた。収率:400mg、0.94mmol、84%。LCMS m/z 424.0 [M+H+].
生成物は、4−クロロ−5−ヨード−2−メチル−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C23)から、実施例6で3−{4−[(2S)−2−メチルモルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル(6)の合成について記載した方法に従って調製した。この場合では、精製をシリカゲルクロマトグラフィー(勾配:0%〜50%の石油エーテル中酢酸エチル)によって実施して、生成物を黄色の油状物として得た。収率:300mg、0.63mmol、67%。LCMS m/z 475.2 [M+H+].
5−ヨード−2−メチル−4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C24)(100mg、0.21mmol)、(3−シアノフェニル)ボロン酸(62mg、0.42mmol)、および炭酸カリウム(100mg、0.72mmol)をエタノールと水の混合物(4:1、5mL)に溶かした溶液に、ジクロロビス(トリフェニルホスフィン)パラジウム(15mg、21μmol)を加えた。反応混合物を脱気し、窒素パージし、この手順を合計3回実施した。反応混合物を90℃で3時間加熱しておいた後、それを冷まし、真空中で濃縮した。分取薄層クロマトグラフィー(溶離液:1:1の石油エーテル/酢酸エチル)によって精製すると、生成物が黄色の油状物として得られた。収率:52mg、0.12mmol、57%。LCMS m/z 451.3 [M+H+].
実施例1で5−(1−メチル−1H−ピラゾール−4−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン(1)の合成について記載した方法を使用して、3−[2−メチル−4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(C25)を生成物に変換した。この場合では、分取HPLC精製は、Phenomenex Gemini C18 カラム、8μm;移動相A:水中アンモニア、pH10;移動相B:アセトニトリル、勾配:30%〜50%のBを使用して実施した。生成物は、白色の固体として得られた。収率:17.3mg、54.2μmol、2ステップで45%。LCMS m/z 320.1 [M+H+].
1H NMR (400MHz, CD3OD)δ7.91-7.93 (m, 1H), 7.85-7.88 (m,
1H), 7.60-7.69 (m, 2H), 7.38 (s, 1H), 3.51-3.55 (m, 4H), 3.24-3.28 (m, 4H),
2.59 (s, 3H).
{3−[4−(ジメチルアミノ)−7H−ピロロ[2,3−d]ピリミジン−5−イル]フェニル}メタノール(10)
5−ヨード−N,N−ジメチル−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−4−アミン(C3)(418mg、1.00mmol)、[3−(ヒドロキシメチル)フェニル]ボロン酸(228mg、1.50mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0)(115mg、0.100mmol)、および炭酸セシウム(625mg、1.92mmol)を1,4−ジオキサン(6mL)および水(1.5mL)に溶かした溶液を、窒素パージし、次いでマイクロ波照射のもと120℃で20分間加熱した。反応混合物を飽和塩化ナトリウム水溶液(50mL)で希釈し、ジクロロメタン(3×60mL)で抽出した。有機層を合わせて硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮した。シリカゲルでのクロマトグラフィー(勾配:2%〜17%の石油エーテル中酢酸エチル)にかけると、生成物が褐色の油状物として得られた。収率:369mg、0.926mmol、93%。LCMS m/z 399.0 [M+H+].
{3−[4−(ジメチルアミノ)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル]フェニル}メタノール(C26)(397mg、0.996mmol)のトリフルオロ酢酸(10mL)溶液を、室温で2時間撹拌した。反応混合物を真空中で濃縮して、生成物(400mg)を褐色の油状物として得た。この材料をそのまま次のステップに持ち込んだ。LCMS m/z 395.1 [M+H+].
3−[4−(ジメチルアミノ)−7−(ヒドロキシメチル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンジルトリフルオロアセテート(C27)(先行ステップより、400mg、0.996mmol以下)および炭酸カリウム(500mg、3.6mmol)のメタノール(10mL)中混合物を、80℃で30分間撹拌した。反応混合物を飽和塩化ナトリウム水溶液(50mL)で希釈し、ジクロロメタン(3×60mL)で抽出し、有機層を合わせて硫酸ナトリウムで乾燥させ、濾過し、真空中で濃縮した。分取HPLC(カラム:Phenomenex Gemini C18、8μm;移動相A:水中アンモニア、pH10;移動相B:アセトニトリル、勾配:21%〜33%のB)によって精製すると、生成物が白色の固体として得られた。収率:77.7mg、0.290mmol、2ステップで29%。LCMS m/z 268.9 [M+H+]. 1H NMR (400MHz, CDCl3)δ10.83
(br s, 1H), 8.39 (s, 1H), 7.50 (br s, 1H), 7.38-7.42 (m, 2H), 7.29-7.34 (m,
1H), 7.11 (s, 1H), 4.78 (s, 2H), 2.84 (s, 6H).
3−[6−(ジフルオロメチル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(198)
ジイソプロピルアミン(2.9g、29mmol)のテトラヒドロフラン(30mL)溶液を−78℃に冷却し、n−ブチルリチウム(2.5M、11.6mL、29mmol)を滴下して処理した。反応混合物を0℃で1時間撹拌し、次いで−78℃に冷却した。4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C1)(8.0g、20mmol)のテトラヒドロフラン(10mL)溶液を滴下し、−78℃で1時間撹拌を続けた。−78℃の反応混合物に、ギ酸エチル(2.6g、35mmol)のテトラヒドロフラン(10mL)溶液を滴下した後、それを室温に温め、18時間撹拌した。次いでそれを0℃に冷却し、飽和塩化アンモニウム水溶液(20mL)を加えて反応を失活させ、次いで酢酸エチル(3×50mL)で抽出した。有機層を合わせて飽和塩化ナトリウム水溶液(50mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮した。シリカゲルクロマトグラフィー(勾配:0%〜25%の石油エーテル中酢酸エチル)によって精製すると、生成物が黄色の油状物として得られた。収率:5.0g、11mmol、55%。1H NMR (400MHz, CDCl3)δ10.11
(s, 1H), 8.80 (s, 1H), 6.05 (s, 2H), 3.55-3.62 (m, 2H), 0.89-0.96 (m, 2H),
-0.05 (s, 9H).
4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−6−カルバルデヒド(C28)(5.0g、11mmol)のアセトニトリル(20mL)溶液に、モルホリン(1.09g、12.5mmol)およびN,N−ジイソプロピルエチルアミン(2.94g、22.7mmol)を加えた。反応混合物を還流温度で16時間撹拌し、その後それを冷却し、真空中で濃縮し、残渣をシリカゲルでのクロマトグラフィー(勾配:0%〜20%の石油エーテル中酢酸エチル)によって精製して、生成物を黄色の油状物として得た。収率:4.0g、8.2mmol、74%。1H NMR (400MHz, CDCl3)δ9.99
(s, 1H), 8.54 (s, 1H), 6.01 (s, 2H), 3.92-3.98 (m, 4H), 3.70-3.75 (m, 4H),
3.58-3.65 (m, 2H), 0.91-0.96 (m, 2H), -0.05 (s, 9H).
実施例2で3−(4−クロロ−6−メチル−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル)ベンゾニトリル(C7)の合成について記載した方法を使用して、5−ヨード−4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−6−カルバルデヒド(C29)を生成物に変換した。生成物は、黄色の固体として得られた。収率:1.5g、3.2mmol、78%。1H NMR (400MHz, CDCl3)δ9.75
(s, 1H), 8.60 (s, 1H), 7.77-7.83 (m, 2H), 7.72-7.76 (m, 1H), 7.67 (br dd, J=8,
8Hz, 1H), 6.09 (s, 2H), 3.66-3.71 (m, 2H), 3.38-3.44 (m, 4H), 3.23-3.28 (m,
4H), 0.94-1.01 (m, 2H), -0.03 (s, 9H).
3−[6−ホルミル−4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(C30)(200mg、0.43mmol)および三フッ化(ジエチルアミノ)硫黄(276mg、1.71mmol)のジクロロメタン(10mL)溶液を、40℃で16時間撹拌した。反応混合物を飽和炭酸水素ナトリウム水溶液(10mL)中に注ぎ、ジクロロメタン(3×20mL)で抽出した。有機層を合わせて飽和塩化ナトリウム水溶液(50mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮し、シリカゲルでの分取薄層クロマトグラフィー(溶離液:1:1の酢酸エチル/石油エーテル)によって精製すると、生成物が黄色の固体として得られた。収率:150mg、0.31mmol、72%。1H NMR (400MHz, CDCl3)δ8.58
(s, 1H), 7.76 (ddd, J=7.3, 1.6, 1.5Hz, 1H), 7.72-7.74 (m, 1H), 7.61-7.70 (m,
2H), 6.74 (t, JHF=52.5Hz, 1H), 5.86 (s, 2H), 3.65-3.72 (m, 2H),
3.34-3.42 (m, 4H), 3.15-3.21 (m, 4H), 0.95-1.02 (m, 2H), -0.02 (s, 9H).
3−[6−(ジフルオロメチル)−4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(C31)(10mg、21μmol)のトリフルオロ酢酸(2mL)溶液を、室温で24時間撹拌した。反応混合物を濃縮し、分取逆相高速液体クロマトグラフィー(カラム:DIKMA Diamonsil(2)C18、5μm、溶離液:0.225%のギ酸を含有する22%の水中アセトニトリル)によって精製して、生成物を白色の固体として得た。収率:2.0mg、5.6μmol、27%。LCMS m/z 355.9 [M+H+]. 1H
NMR (400MHz, DMSO-d6)δ13.06 (br s, 1H), 8.47 (s, 1H), 7.92 (ddd,
J=6.7, 2.1, 1.7Hz, 1H), 7.83-7.85 (m, 1H), 7.69-7.76 (m, 2H), 7.02 (t, JHF=52.5Hz,
1H), 3.22-3.30 (m, 4H), 3.03-3.10 (m, 4H).
5−(5,6−ジヒドロ−2H−ピラン−3−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン(199)および5−(3,4−ジヒドロ−2H−ピラン−5−イル)−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン(200)
−78℃の4−クロロ−5−ヨード−7H−ピロロ[2,3−d]ピリミジン(1.5g、5.4mmol)のテトラヒドロフラン(50mL)溶液に、n−ブチルリチウム(2.5M、6.4mL、16.1mmol)を滴下した。反応混合物を−78℃で2時間撹拌しておいた後、それをジヒドロ−2H−ピラン−3(4H)−オン(1.61g、16.1mmol)で処理し、室温に温め、18時間撹拌した。水(50mL)で反応を失活させ、水層を酢酸エチル(3×30mL)で抽出し、有機層を合わせて飽和塩化ナトリウム水溶液(100mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮した。シリカゲルクロマトグラフィー(勾配:0%〜50%の石油エーテル中酢酸エチル)にかけると、生成物が黄色の油状物として得られた。収率:200mg、0.79mmol、15%。LCMS m/z 254.0 [M+H+].
3−(4−クロロ−7H−ピロロ[2,3−d]ピリミジン−5−イル)テトラヒドロ−2H−ピラン−3−オール(C32)(200mg、0.79mmol)およびモルホリン(134mg、1.54mol)のn−ブタノール(10mL)溶液に、N,N−ジイソプロピルエチルアミン(305mg、2.36mol)を加え、反応混合物を70℃で2時間加熱した。真空中で濃縮した後、分取逆相高速液体クロマトグラフィー(カラム:Phenomenex Gemini C18、8μm;移動相A:アンモニア水溶液、pH10;移動相B:アセトニトリル、勾配:9%〜29%のB)にかけると、生成物が白色の固体として得られた。収率:180mg、0.59mmol、75%。LCMS m/z 305.1 [M+H+]. 1H NMR (400MHz, CDCl3
+ D2O)δ8.73 (s, 1H), 7.52 (s, 1H), 3.92-4.03 (m, 4H), 3.74-3.88 (m,
4H), 3.32-3.40 (m, 2H), 3.15-3.24 (m, 2H), 2.07-2.16 (m, 1H), 1.88-2.06 (m,
2H), 1.57-1.68 (m, 1H).
3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]テトラヒドロ−2H−ピラン−3−オール(C33)(40mg、0.13mmol)のジクロロメタン(10mL)溶液に、トリエチルシラン(10mL)およびトリフルオロ酢酸(10mL)を10分かけて加えた。反応混合物を室温で2時間撹拌し、その後それを真空中で濃縮した。分取逆相高速液体クロマトグラフィー(カラム:Boston Symmetrix ODS−H、5μm;移動相A:0.225%のギ酸を含有する水;移動相B:アセトニトリル、勾配:11%〜31%のB)にかけると、199が白色の固体(収率:11.3mg、39.5μmol、30%)として、200も白色の固体(収率:7.0mg、24μmol、18%)として得られた。
199:LCMS m/z 287.0 [M+H+]. 1H NMR (400MHz, DMSO-d6)δ11.97
(br s, 1H), 8.29 (s, 1H), 7.31 (s, 1H), 5.87-5.93 (m, 1H), 4.30-4.36 (m, 2H),
3.68-3.78 (m, 6H), 3.36-3.43 (m, 4H), 2.21-2.29 (m, 2H).
200:LCMS m/z 287.0 [M+H+]. 1H NMR (400MHz, DMSO-d6)δ11.83
(br s, 1H), 8.26 (s, 1H), 7.18 (s, 1H), 6.65 (s, 1H), 3.92-3.97 (m, 2H), 3.69-3.76
(m, 4H), 3.40-3.46 (m, 4H), 2.29-2.36 (m, 2H), 1.88-1.96 (m, 2H).
4−(モルホリン−4−イル)−5−[3−(1,2,4−オキサジアゾール−3−イル)フェニル]−7H−ピロロ[2,3−d]ピリミジン(201)
調製例P1で4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C1)の合成について記載した方法を使用して、3−[4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(4)を生成物に変換した。生成物は、黄色の固体として得られた。収率:0.90g、2.1mmol、70%。1H NMR (400MHz, CDCl3)δ8.55
(s, 1H), 7.86 (br s, 1H), 7.79 (br d, J=7.6Hz, 1H), 7.63 (br d, J=7.6Hz, 1H),
7.57 (dd, J=7.6, 7.6Hz, 1H), 7.29 (s, 1H), 5.67 (s, 2H), 3.58-3.64 (m, 2H),
3.52-3.58 (m, 4H), 3.27-3.32 (m, 4H), 0.92-0.98 (m, 2H), -0.03 (s, 9H).
3−[4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゾニトリル(C34)(436mg、1.00mmol)をエタノール(10mL)および水(5mL)に溶かした撹拌した溶液に、ヒドロキシルアミン塩酸塩(278mg、4.00mmol)および炭酸ナトリウム(318mg、3.00mmol)を加えた。反応混合物を還流温度で2時間加熱し、次いで真空中で濃縮し、水(25mL)中に注ぎ、酢酸エチル(3×10mL)で抽出した。有機層を合わせて飽和塩化ナトリウム水溶液(25mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮して、生成物を白色の固体として得た。収率:280mg、0.60mmol、60%。1H NMR (400MHz, DMSO-d6)δ9.67
(s, 1H), 8.43 (s, 1H), 7.89 (br s, 1H), 7.72 (s, 1H), 7.64 (br d, J=7.8Hz, 1H),
7.53 (br d, J=7.8Hz, 1H), 7.46 (dd, J=7.6, 7.6Hz, 1H), 5.89 (br s, ~1.6H), 5.61
(s, 2H), 3.53-3.61 (m, 2H), 3.39-3.47 (m, 4H), 3.13-3.21 (m, 4H), 0.81-0.88 (m,
2H), -0.09 (s, 9H).
0℃のN’−ヒドロキシ−3−[4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−5−イル]ベンゼンカルボキシミドアミド(C35)(600mg、1.3mmol)のテトラヒドロフラン(25mL)溶液に、オルトギ酸トリエチル(760mg、5.1mol)および三フッ化ホウ素ジエチルエーテラート(370mg、2.6mol)を加えた。反応混合物を40℃で18時間加熱し、次いで水(50mL)中に注ぎ、酢酸エチル(3×25mL)で抽出した。有機層を合わせて飽和塩化ナトリウム水溶液(50mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮した。分取逆相高速液体クロマトグラフィー(カラム:Phenomenex Gemini C18、8μm;移動相A:アンモニア水溶液、pH10;移動相B:アセトニトリル、勾配:30%〜50%のB)によって精製すると、生成物が黄色の固体として得られた。収率:62mg、0.18mmol、14%。LCMS m/z 349.0 [M+H+]. 1H NMR (400MHz, DMSO-d6)δ9.77
(s, 1H), 8.40 (s, 1H), 8.24 (br s, 1H), 7.98 (br d, J=7.5Hz, 1H), 7.82 (br d,
J=7.3Hz, 1H), 7.63-7.70 (m, 2H), 3.39-3.45 (m, 4H), 3.13-3.20 (m, 4H).
3−{4−[2−(3−メチル−1,2−オキサゾール−5−イル)モルホリン−4−イル]−7H−ピロロ[2,3−d]ピリミジン−5−イル}ベンゾニトリル(202)
2−ブロモ−1−(3−メチル−1,2−オキサゾール−5−イル)エタノン(2.50g、12.2mmol)および2−(ベンジルアミノ)エタノール(3.70g、24.5mmol)のアセトニトリル(25mL)溶液を、35℃で18時間撹拌した。反応混合物を真空中で濃縮し、シリカゲルクロマトグラフィー(勾配:0%〜50%の石油エーテル中酢酸エチル)を使用して精製して、生成物を黄色の油状物として得た。収率:1.2g、4.4mmol、36%。1H NMR (400MHz, CDCl3)δ7.27-7.38
(m, 5H), 6.22 (s, 1H), 4.11-4.19 (m, 1H), 3.76-3.84 (m, 1H), 3.60 (AB四重線, JAB=13.0Hz, ΔνAB=13.2Hz, 2H), 2.99 (br d,
J=11.0Hz, 1H), 2.71-2.79 (m, 1H), 2.55 (d, J=11.0Hz, 1H), 2.42 (ddd, J=11.7,
11.5, 3.6Hz, 1H), 2.29 (s, 3H).
4−ベンジル−2−(3−メチル−1,2−オキサゾール−5−イル)モルホリン−2−オール(C36)(1.2g、4.4mmol)のジクロロメタン(15mL)溶液に、トリフルオロメタンスルホン酸トリメチルシリル(2.9g、13mmol)およびトリエチルシラン(2.6g、22mmol)を加え、反応混合物を80℃で2時間加熱した。次いで、飽和炭酸水素ナトリウム水溶液を加えることで、反応混合物をpH約5〜6に調整した。ジクロロメタン(3×20mL)で抽出した後、有機層を合わせて飽和塩化ナトリウム水溶液(25mL)で洗浄し、硫酸ナトリウムで乾燥させ、濾過し、濃縮した。シリカゲルクロマトグラフィー(勾配:0%〜50%の石油エーテル中酢酸エチル)によって精製すると、生成物が黄色の油状物として得られた。収率:500mg、1.9mmol、43%。LCMS m/z 258.9 [M+H+]. 1H NMR (400MHz, CDCl3)δ7.27-7.37
(m, 5H), 6.07 (s, 1H), 4.75 (dd, J=9.7, 2.3Hz, 1H), 3.96 (ddd, J=11.3, 2.8,
2.4Hz, 1H), 3.81 (ddd, J=11.3, 10.8, 2.5Hz, 1H), 3.52-3.61 (m, 2H), 3.02 (br d,
J=11.4Hz, 1H), 2.68-2.75 (m, 1H), 2.29 (s, 3H), 2.27-2.37 (m, 2H).
4−ベンジル−2−(3−メチル−1,2−オキサゾール−5−イル)モルホリン(C37)(100mg、0.39mmol)のアセトニトリル/水(5:1混合物、6mL)溶液に、硝酸アンモニウムセリウム(IV)(442mg、0.806mmol)を加えた。反応混合物を25℃で4時間撹拌し、次いで真空中で濃縮し、シリカゲルでの分取薄層クロマトグラフィー(溶離液:10:1のジクロロメタン/メタノール)にかけると、生成物が黄色の油状物として得られた。収率:40mg、0.24mmol、62%。1H NMR (400MHz, CDCl3)δ6.11
(s, 1H), 4.79 (dd, J=10.0, 2.4Hz, 1H), 4.01 (ddd, J=11.8, 2.5, 2.4Hz, 1H),
3.81-3.89 (m, 1H), 3.35 (dd, J=12.7, 2.5Hz, 1H), 2.99-3.07 (m, 3H), 2.30 (s,
3H).
2−(3−メチル−1,2−オキサゾール−5−イル)モルホリン(C38)(20mg、0.12mmol)のn−ブタノール(7mL)溶液に、3−(4−クロロ−7H−ピロロ[2,3−d]ピリミジン−5−イル)ベンゾニトリル(C14)(36.2mg、0.142mol)を加え、反応混合物を封管に入れ、マイクロ波反応器において150℃で2時間加熱した。溶媒を除去した後、残渣を、分取逆相高速液体クロマトグラフィー(カラム:YMC−Actus Triart C18、5μm;移動相A:0.225%のギ酸を含有する水;移動相B:アセトニトリル、勾配:33%〜53%のB)によって精製して、生成物を白色の固体として得た。収率:0.78mg、2.0μmol、2%。LCMS m/z 387.0 [M+H+]. 1H
NMR (400MHz, DMSO-d6), 特徴的ピーク:δ12.45 (br s,
1H), 8.45 (s, 1H), 8.00-8.03 (m, 1H), 7.85 (br d, J=8Hz, 1H), 7.76 (br d,
J=8Hz, 1H), 7.72 (d, J=2.8Hz, 1H), 7.66 (dd, J=8, 8Hz, 1H), 6.25 (s, 1H),
4.58-4.63 (m, 1H), 3.71-3.83 (m, 2H), 3.01-3.09 (m, 1H), 2.88-2.97 (m, 1H),
2.20 (s, 3H).
方法A
塩化物置換による3−(4−クロロ−7H−ピロロ[2,3−d]ピリミジン−5−イル)ベンゾニトリルへの4−アミノ置換基の導入
鈴木反応による5−置換−4−[(3S)−3−メチルピペリジン−1−イル]−7H−ピロロ[2,3−d]ピリミジンの合成
適切なボロン酸エステルを1,4−ジオキサン水溶液(1:5v/vの水/1,4−ジオキサン)に溶かした溶液(0.3M、400μL、120μmol)を、5−ヨード−4−[(3S)−3−メチルピペリジン−1−イル]−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(P5)(1:5の水/1,4−ジオキサン中0.25M、400μL、100μmol)と合わせた。溶液を炭酸セシウム(65mg、200μmol)で処理し、窒素を通気することにより脱気した。反応混合物に[1,1’−ビス(ジ−tert−ブチルホスフィノ)フェロセン]ジクロロパラジウム(II)(3mg、5μmol)を加え、これを再び窒素で脱気し、次いで150℃で4時間振盪した。Speedvac(登録商標)濃縮装置を使用して溶媒を除去した後、生成物を適切な溶媒系での分取薄層クロマトグラフィーによって精製し、次のステップに送った。
先行ステップからの生成物をトリフルオロ酢酸のジクロロメタン溶液(1:5v/v、2mL)で処理し、反応混合物を30℃で2時間振盪した。Speedvac(登録商標)を使用して濃縮した後、残渣を水酸化アンモニウムのメタノール溶液(1:4v/v、2mL)で処理し、30℃で16時間振盪した。Speedvac(登録商標)で溶媒を除去し、生成物を、適切な勾配を使用する分取HPLC(カラム:DIKMA Diamonsil(2)C18、5μmまたはAgella Venusil ASB C18、5μm;移動相A:0.225%の水中ギ酸;移動相B:アセトニトリル)によって精製した。
鈴木反応による5−置換−4−(モルホリン−4−イル)−7H−ピロロ[2,3−d]ピリミジンの合成
5−ヨード−4−(モルホリン−4−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(P1)の1,4−ジオキサン溶液(0.20M、400μL、80μmol)を、適切なボロン酸の1,4−ジオキサン溶液(0.50M、200μL、100μmol)と合わせた。リン酸カリウムの水溶液(0.80M、200μL、160μmol)を加えた後、[1,1’−ビス(ジ−tert−ブチルホスフィノ)フェロセン]ジクロロパラジウム(II)(3mg、5μmol)を加え、反応混合物を100℃で16時間振盪した。混合物を濾過し、濾液をSpeedvac(登録商標)で濃縮した。残渣をジクロロメタンと飽和炭酸ナトリウム水溶液とに分配し、水層をジクロロメタン(2×1mL)で抽出した。有機層を合わせて硫酸ナトリウムで乾燥させ、濾過し、Speedvac(登録商標)を使用して濃縮して粗生成物を得、これをそのまま次のステップで使用した。
先行反応の生成物を濃塩酸のエタノール溶液(1:6v/v、1mL)で処理し、反応混合物を80℃で16時間振盪した。Speedvac(登録商標)で溶媒を除去した後、残渣を、次の系、すなわち、1)カラム:Kromasil Eternity−5−C18、5μmまたはBoston Symmetrix ODS−H、5μmまたはPhenomenex Synergi C18、4μm;移動相A:0.225%の水中ギ酸;移動相B:アセトニトリル、2)カラム:Phenomenex Gemini C18、8μm;移動相A:水酸化アンモニウム水溶液、pH10;移動相B:アセトニトリルの一方を用いた、適切な勾配を使用する分取HPLCによって精製した。
塩化物置換による7H−ピロロ[2,3−d]ピリミジンへの4−アミノ置換基の導入
4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジンからの4−アミノ置換された5−置換−7H−ピロロ[2,3−d]ピリミジンの合成
適切なアミン(150μmol)に、4−クロロ−5−ヨード−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン(C1)のN,N−ジメチルホルムアミド溶液(0.25M、500μL、125μmol)を加えた。トリエチルアミン(35μL、250μmol)を加え、反応混合物を100℃で16時間振盪した。この溶液をそのまま次のステップで使用した。
先行ステップからの生成物溶液(125μmol以下)を適切なボロン酸のN,N−ジメチルホルムアミド溶液(0.25M、500μL、125μmol)と混合した。炭酸セシウムの水溶液(1.25M、200μL、250μmol)を加えた後、[1,1’−ビス(ジ−tert−ブチルホスフィノ)フェロセン]ジクロロパラジウム(II)(1.6mg、2.5μmol)を加え、反応混合物を120℃で4時間振盪した。Speedvac(登録商標)を使用して溶媒を除去すると残渣が得られ、これをそのまま次のステップで使用した。
先行ステップからの生成物(125μmol以下)を、濃塩酸のエタノール溶液(1:6v/v、2mL)で処理し、反応混合物を80℃で16時間振盪した。Speedvac(登録商標)で溶媒を除去した後、残渣を、水酸化アンモニウム(30%水溶液)のメタノール溶液(1:4v/v、2mL)に溶かした。混合物を30℃で16時間振盪し、Speedvac(登録商標)で濃縮し、適切な勾配を使用する分取HPLC(カラム:DIKMA Diamonsil(2)C18、5μmまたはAgella Venusil ASB C18、5μm;移動相A:0.225%の水中ギ酸;移動相B:アセトニトリル)によって精製した。
鈴木反応による5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン−4−アミンへの5−置換基の導入
適切なハロゲン化アリールまたはヘテロアリール(100μmol)に、5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−7−{[2−(トリメチルシリル)エトキシ]メチル}−7H−ピロロ[2,3−d]ピリミジン基体の1,4−ジオキサン溶液(0.1M、1mL、100μmol)を加えた。炭酸セシウムの水溶液(1.0M、200μL、200μmol)を加えた後、[1,1’−ビス(ジ−tert−ブチルホスフィノ)フェロセン]ジクロロパラジウム(II)(1.3mg、2.0μmol)を加え、反応混合物を120℃で4時間振盪した。Speedvac(登録商標)を使用して溶媒を除去すると残渣が得られ、これをそのまま次のステップで使用した。
保護基の除去および精製は、方法Eの最終ステップに記載のとおりに行った。
LRRK2アッセイ
LRRK2キナーゼ活性は、InvitrogenのLantha Screen技術を使用して測定した。InvitrogenのGSTタグ付き切断型LRRK2(カタログ番号PV4874)を、化合物の用量反応液の存在下、LRRKtideとしても知られているエズリン/ラディキシン/モエシン(ERM)を主体とするペプチド基質をフルオレセインで標識したもの(Invitrogenカタログ番号PR8976A)と共にインキュベートした。完了した後、アッセイを中断し、テルビウム標識抗ホスホERM抗体(Invitrogen、カタログ番号PR8975A)で検出した。アッセイは、次のプロトコールに従って実施した。アッセイ緩衝液(2mMのDTTおよび0.01%のBrij35を新たに加えた、50mMのHEEPES、pH7.5、3mMのMgCl2)中に調製した基質の標準溶液(working solution)(233nMのLRRKtide、117μMのATP)3μLを、低用量Greiner 384ウェルプレートに加えた。化合物用量反応液は、化合物を100%DMSOで3.16mMの最高濃度に希釈することにより調製し、DMSO中に11回半対数連続希釈した。100%DMSO用量反応液の分割量(3.5μL)を46.5μLの水と混合し、次いで、この混合物1μLを、384ウェルプレート中の3μLの基質混合物に加えた。4μg/mLの濃度のLRRK2酵素の標準溶液3μLによってキナーゼ反応を開始した。最終反応液濃度は、100nMのLRRKtide、50μMのATP、1.7μg/mLのLRRK2酵素、および最高用量32μMの化合物用量反応液であった。室温で2時間反応を進行させ、次いで7μLの検出緩衝液(20mMのTris pH7.6、0.01%のNP−40、0.02%のNaN3、6mMのEDTA、2nMのテルビウム標識抗ホスホERM)を加えて停止させた。室温で1時間インキュベートした後、Envisionにおいて、340nmの励起波長、520nmおよび495nmの読取り発光でプレートを読み取った。520nmの発光と495nmの発光の比を使用してデータを解析した。
Claims (2)
- 式Iの化合物
または薬学的に許容できるその塩[式中、
R 1およびR2は、これらが結合している窒素と合わせて、
R3は、1−メチルピラゾール−4−イル、1H−ピラゾール−4−イル、2−シアノピリジン−6−イル、3−メチル−1,2−チアゾール−5−イル、5−シアノ−1−メチルピロール−3−イル、3−メチルピリジン−5−イル、3−シアノフェニル、2−フルオロフェニル、3−フルオロフェニル、2,3−ジフルオロフェニル、2−フルオロ−5−クロロフェニル、2−フルオロ−3−シアノフェニルまたは2−メトキシ−5−フルオロフェニルであり
R4およびR5は、それぞれ独立に、水素またはメチルである]。 - 治療有効量の請求項1に記載の化合物または薬学的に許容できるその塩を、薬学的に許容できる担体と共に含む、がんを治療するために用いるための、医薬組成物。
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